This action might not be possible to undo. Are you sure you want to continue?
N Engl J Med. Author manuscript; available in PMC 2011 June 6.
Published in final edited form as: N Engl J Med. 2010 June 24; 362(25): 2389–2398. doi:10.1056/NEJMcp1000274.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Endometriosis Linda C. Giudice, M.D., Ph.D. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco
A healthy 25-year-old woman presents with worsening dysmenorrhea, pain of recent onset in the left lower quadrant, and dyspareunia. She has regular menstrual cycles, and her last menstrual period was 3 weeks before presentation. How should this patient be evaluated and treated?
THE CLINICAL PROBLEM
Endometriosis, a major contributor to pelvic pain and subfertility,1 is characterized by endometrial-like tissue outside the uterus (Fig. 1), primarily on the pelvic peritoneum, ovaries, and rectovaginal septum, and in rare cases on the diaphragm, pleura, and pericardium. Endometriosis affects 6 to 10% of women of reproductive age, 50 to 60% of women and teenage girls with pelvic pain, and up to 50% of women with infertility.2,3 Peritoneal disease, which is dependent on estrogen for growth, derives from retrograde menstruation of steroid hormone–sensitive endometrial cells and tissues (Fig. 2), which implant on peritoneal surfaces and elicit an inflammatory response. This response is accompanied by angiogenesis, adhesions, fibrosis, scarring, neuronal infiltration, and anatomical distortion (Fig. 1 and 2), resulting in pain and infertility.1,4–6 Although most women have retrograde menstruation, not all women with retrograde menstruation have endometriosis; affected women may have an immune dysfunction that interferes with clearing of the lesions.1 Since ovarian endometriomas are clonal and lesions can have genetic mutations, somatic mutations with resulting growth dysregulation also may be etiologic factors.1,4 Disease at distant sites is probably caused by lymphatic or hematogenous spread or meta-plastic transformation. Risk factors for endometriosis include obstruction of menstrual outflow (e.g., mullerian anomalies7), exposure to diethylstilbestrol in utero,8 prolonged exposure to endogenous estrogen (e.g., because of early menarche, late menopause, or obesity), short menstrual cycles, low birth weight,9 and exposure to endocrine-disrupting chemicals.10 Twin and family studies suggest a genetic component.11 Consumption of red meat and trans fats is associated with an increased risk of laparoscopically confirmed endometriosis, and eating
Copyright © 2010 Massachusetts Medical Society Address reprint requests to Dr. Giudice at the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, 505 Parnassus Ave., M1491, San Francisco, CA 94143-0132, or at email@example.com.. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations. Dr. Giudice reports receiving consulting fees from Bayer Schering Pharma, Neurocrine Biosciences, Endo Pharmaceuticals, and Schering-Plough, holding stock in Merck and Pfizer, and serving on advisory committees for the Endometriosis Association and Baylor College of Medicine. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
myofascial pain. with ranges of 80 to 90% sensitivity and 60 to 98% specificity22 (Fig. leiomyomata.9 Endometriosis is associated with increased risks of autoimmune diseases and ovarian endometrioid and clear-cell cancers. irritable bowel syndrome.. indicating minimal disease. social. Doppler N Engl J Med. 1). to IV. including non-Hodgkin's lymphoma and melanoma. dyspareunia. However. as well as other cancers. making diagnosis challenging. women report burning or hypersensitivity. available in PMC 2011 June 6. surgical. and it can be dull. appearance. deep pelvic pain.12 Prolonged lactation and multiple pregnancies are protective. indicating severe disease) on the basis of the type. ovarian cysts or masses.21 Nonsurgical diagnostic approaches such as transvaginal ultrasonography and magnetic resonance imaging (MRI) perform poorly in the detection of peritoneal and ovarian implants and adhesions. interstitial cystitis. and 9 to 59% are stable over a 12-month period.org). depression.. 24 to 64% progress. inflammatory bowel disease. and a history of sexual abuse). the estimated costs of diagnosing endometriosis and treating associated pain and infertility totaled $22 billion in 2002. green vegetables. pelvic adhesions.19 DIAGNOSIS AND CLINICAL STAGING Currently.and bowelassociated symptoms (nausea.19 Bladder. and rectovaginal nodules are suggestive of endometriosis but are not diagnostic because of their poor sensitivity and specificity. and adenomyosis) and nongynecologic conditions and factors (e.1 Follow-up of women with pelvic pain and laparoscopically identified disease has shown that 17 to 29% of lesions resolve spontaneously.14 In the United States. the stage does not correlate with the severity of pain or predict the response to therapies for pain or infertility. An evaluation of both the female patient and her male partner is indicated in cases of associated infertility. The pain can occur unpredictably and intermittently throughout the menstrual cycle or it can be continuous.20 Symptoms overlap with those of several other gynecologic conditions (e. location.17 A pelvic mass. Although staging is useful in determining disease burden and management. and n−3 long-chain fatty acids is associated with a decreased risk. pelvic inflammatory disease.16.16.19 Pain often worsens over time and may change in character. and depth of invasion of the lesions and the extent of disease and adhesions (see the table in the Supplementary Appendix. 3). throbbing. infrequently.g. and early satiety) are typically cyclic. Author manuscript. and family history should be obtained from patients who present with this symptom.16 A complete medical. and they should undergo a physical examination that includes a pelvic examination. or sharp. immobile pelvic organs. Because of its lower cost.13 Endometriosis is a major cause of disability and compromised quality of life in women and teenage girls. symptoms that are suggestive of a neuropathic component. available with the full text of this article at NEJM. transvaginal ultrasonography is preferred over MRI in the diagnosis of endometriomas. and lower abdominal pain with or without back and loin pain. The revised scoring system of the American Society for Reproductive Medicine is used to determine the disease stage (ranging from I.15 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript STRATEGIES AND EVIDENCE EVALUATION Chronic pelvic pain accounts for 10% of outpatient gynecologic visits. distention. and exacerbated by physical acitivity.16. Focal pain or tenderness on pelvic examination is associated with pelvic disease in 97% of patients and with endometriosis in 66% of patients.Giudice Page 2 fruits.18 Pelvic pain due to endometriosis is usually chronic (lasting ≥6 months) and is associated with dysmenorrhea (in 50 to 90% of cases).g. the definitive method to diagnose and stage endometriosis and evaluate the recurrence of disease after treatment is visualization at surgery21 (Fig. . both imaging methods perform well in detecting ovarian endometriomas.
a switch to continuous combined oral contraceptives reduced pain scores by 58% within 6 months and by 75% at 2 years (P<0. In women with severe dysmenorrhea who have been treated with cyclic combined oral contraceptives. and amenorrhea.04). P = 0. or both.4 years. P<0.30 GnRH agonists effectively deplete the pituitary of endogenous gonadotropins and inhibit further synthesis.23 The mean interval between the onset of pain and definitive (surgical) diagnosis is 10. scores for pelvic pain. 3A) may help in establishing the diagnosis. controlled trial showed no significant reduction in pain due to endometriosis with the use of NSAIDs as compared with placebo and no superiority of one NSAID over another. although one randomized.Giudice Page 3 ultrasonography (Fig.19.22 Levels of CA-125 may be elevated in endometriosis.25 Medical Therapy—Empirical medical therapy is commonly initiated for pain control without surgical confirmation of disease. available in PMC 2011 June 6. inhibiting the action and synthesis of estradiol. interrupting or suppressing cyclic ovarian hormone production. which induces endometrial atrophy and associated amenorrhea. . endometrial atrophy. in randomized.28 Head-to-head randomized. 32%. A randomized. thus interrupting the menstrual cycle and resulting in a hypoestrogenic state. tenderness. nonblinded studies. and dysmenorrhea improved with the use of regimens combining norethindrone acetate at a dose of 5 mg daily with a GnRH agonist. improvement in pain scores for dysmenorrhea with the use of GnRH agonists was 60 to 100%. these findings are similar to those with the use of danazol. and enhanced flow to an ovarian tumor. antiprogestins.32 The “estrogen threshold hypothesis”33 suggests that maintaining estradiol levels between 30 and 45 pg per milliliter (109 and 164 pmol per liter) will maintain bone mineral density without stimulating disease.25 This approach is first-line therapy in patients without contraindications to the use of combined oral contraceptives. 14 to 17%.19. estrogen–progestagen add-back therapies are recommended. and combined oral contraceptives.24 PAIN MANAGEMENT Long-term treatment of patients with chronic pelvic pain associated with endometriosis involves repeated courses of medical therapy. although they are associated with a 20 to 25% failure rate. including a hypoestrogenic state that may lead to bone loss of up to 13% over a period of 6 months (which is partly reversible on discontinuation of therapy).19.001) and the volume of ovarian endometriomas (by 48% vs.001). Author manuscript. it shows characteristically scant blood flow to an endometrioma. nonblinded trials have shown that medroxyprogesterone acetate is as effective in controlling pain as combined oral contraceptives. In most cases. including minimizing inflammation.29 In addition.25 Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used to relieve dysmenorrhea. Such therapy is intended to reduce pain through a variety of mechanisms. Table 1 summarizes the indications for and side effects of various agents and approaches to the control of pain due to endometriosis. pain recurs within 6 to 12 months after completion of treatment. diminished endometriosis-associated pain and dysmenorrhea. a NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript N Engl J Med. and reducing or eliminating menses. normal flow to normal ovarian tissue. the levonorgestrel intrauterine system. but this test is not recommended for diagnostic purposes because of poor sensitivity and specificity.31 Since GnRH agonist therapy has considerable side effects. In a systematic review of 15 randomized trials involving 1821 women. surgical therapy.26 Combined oral contraceptives can be used cyclically or continuously for endometriosis-related pain and are commonly combined with NSAIDs. controlled trial27 showed the superiority of combined oral contraceptives over placebo in decreasing baseline pain scores for dysmenorrhea (by 45 to 52% vs. Indeed. as compared with regular follow-up with no treatment or treatment with a gonadotropin-releasing hormone (GnRH) agonist after conservative surgery.
19 Postoperative hormone replacement should include both estrogen and a progestagen. danazol. are not approved by the Food and Drug Administration for endometriosis-related pain. but data from large randomized trials are lacking. or both. or combined oral contraceptives with no postoperative treatment or placebo revealed a significant reduction in pain scores at the NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript N Engl J Med. controlled trials involving 910 women with symptomatic endometriosis revealed that estrogen–progestagen add-back therapy maintained bone density at the lumbar spine during and up to 12 months after GnRH agonist treatment. pain was reported to recur in 10% of the women within 1 to 2 years after surgery. and noncyclic pelvic pain. since estrogen alone may stimulate growth of microscopic disease. A meta-analysis of six randomized trials that compared 3 to 6 months of postoperative treatment with a GnRH agonist. excision or drainage or ablation of endometriomas. available in PMC 2011 June 6. as compared with a 22% rate of pain reduction associated with diagnostic laparoscopy alone. randomized. postoperative medical therapy may improve pain management by providing control of recurrent microscopic or residual disease.38 A combined analysis of data from two randomized trials involving 164 women that compared laparoscopic excision with drainage or ablation of endometriomas larger than 3 cm in diameter showed that excision resulted in less frequent recurrence of dysmenorrhea.39 An alternative strategy for controlling endometriosis-related pain is interruption of nerve pathways. moderate-to-severe dysmenorrhea. however. its androgenic side effects limit its clinical usefulness.34 At 1 year.40 Case series have shown that hysterectomy with bilateral salpingooophorectomy provided pain relief in 80 to 90% of women with debilitating symptoms that were refractory to medical or other surgical interventions.13 A small trial comparing laparoscopic ablation with GnRH agonist treatment showed similar pain reduction with the two approaches. but not when 5 mg of norethindrone acetate was combined with a higher dose (1. Surgical procedures include excision.19. laparoscopic ablation of endometriotic implants is 65% effective in reducing pain. Limited studies involving small numbers of patients have shown that aromatase inhibitors (at doses lower than those used for breast-cancer treatment) are effective in reducing pelvic pain. 2). A meta-analysis of 15 randomized. controlled trials have shown the superiority of laparoscopic ablation of endometriotic tissue combined with presacral neurectomy (removal of the nerve bundle within the boundaries of the interiliac triangle) over laparoscopic ablation alone in improving dysmenorrhea and reducing severe midline pain.20. or laser ablation of endometriotic implants on the peritoneum.29 Recurrence of pain requiring therapy is common (in 30 to 60% of patients) within 6 to 12 months after treatment. dyspareunia. bone mineral density was maintained at baseline levels in all groups that received add-back therapy. Whereas ablation of a segment of the uterosacral ligament has not proved effective. controlled trials have shown that at 6 months.25 mg) of conjugated equine estrogen.37 Aromatase inhibitors. suppression of ovarian estradiol production may not completely control pain. Randomized. Author manuscript.19 Adjunctive Medical Therapy—In women with advanced disease (stage III or IV). and interruption of nerve pathways. as well as reduced rates of further surgery.35 The effects of progestin-only add-back therapy on bone density have been inconsistent in studies involving adults35 and adolescents. Antiprogestagens such as mifepristone have been shown in small studies to reduce pain. however.Giudice Page 4 conjugated equine estrogen at a dose of 0.36 Since endometriotic lesions express aromatase and synthesize their own estradiol (Fig. .29 Surgical Therapy—Surgical approaches to relieve endometriosis-related pain can be used as first-line therapy or initiated after failed medical therapies38 (Table 1). with effects similar to those of other hormonal therapies. Danazol was an early treatment for endometriosis19. lysis of adhesions. and pain. fulguration.625 mg. resection of rectovaginal nodules.
25 In a controlled trial involving 341 women with infertility who underwent diagnostic laparoscopy. A noninvasive diagnostic test with high sensitivity and specificity for endometriosis is lacking. 1. as compared with no treatment before this procedure. these agents are not recommended for the treatment of infertility and should not delay the pursuit of effective fertility therapies.08 to 78.39 although ovarian surgery may diminish ovarian reserve in women with advanced disease. GnRH agonists.25 In a large randomized trial comparing four treatment strategies in 932 couples with stage I or II endometriosis or unexplained infertility.72 to 0.41 The mean interval between surgery and symptom recurrence requiring alternative therapy was significantly longer for patients who received postoperative treatment with GnRH agonists (>24 months) than for patients who received placebo (12 months).42 Thus. controlled trials showed that women with endometriosis were less likely than women with tubal-factor infertility to conceive by means of IVF (odds ratio.41 MANAGEMENT OF INFERTILITY A large meta-analysis of randomized trials evaluating ovarian suppression with combined oral contraceptives.18. cumulative pregnancy rates during four treatment cycles were as follows: intracervical insemination (10%). as well as in vitro fertilization (IVF). intrauterine insemination (18%).44 In a systematic review of three randomized trials including 165 women with advanced endometriosis and infertility. surgical) with respect to pain relief.46 In an observational study involving 216 women with infertility and severe endometriosis.46 A smaller trial did not show a significantly higher pregnancy rate with laparoscopic ablation. A recently proposed scoring system specifically for endometriosis-related chronic pelvic pain48 awaits validation.45 Ablation of endometriotic lesions with lysis of adhesions is recommended for the treatment of infertility related to stage I or II endometriosis. available in PMC 2011 June 6. as compared with 45% among those who had undergone laparoscopy alone. 95% CI. although transcriptomic and proteomic approaches are under study.18. GnRH agonist therapy for 3 to 6 months before IVF.18. or danazol as compared with placebo or no treatment in women with various stages of endometriosis showed no significant differences in spontaneous pregnancy or live birth rates. Author manuscript. 0.25 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript AREAS OF UNCERTAINTY There is a lack of data from randomized trials to inform the optimal management of endometriosis (medical vs.Giudice Page 5 conclusion of therapy in the active-treatment groups. the cumulative pregnancy rate at 2 years was 63% among those who had undergone laparotomy with treatment of lesions and adhesions. as compared with drainage and ablation. although the benefits were inconsistent with longer follow-up (to 18 months) after discontinuation of therapy. and future fertility. 0.25 Gonadotropin therapy and intrauterine insemination.18.47 Two randomized trials showed that excision of endometriomas larger than 3 cm in diameter.19. and gonadotropin therapy and intrauterine insemination (33%).91). are efficacious treatments in women with infertility and endometriosis. significantly increased the live birth rate (odds ratio. but a meta-analysis combining these trials showed a significant difference in rates of pregnancy and live births between groups. 17%). Studies of interventions for pelvic pain often have high rates of placebo effects (approximately 40 to 45% improvement in symptoms). resulted in significantly higher pregnancy rates. pain recurrence. . those randomly assigned to ablation of stage I or II endometriotic lesions had a significantly higher cumulative pregnancy rate at 3 years than untreated patients (31% vs.81. 95% confidence interval [CI]. gonadotropin therapy and intracervical insemination (19%). There is a lack of data from randomized trials evaluating the effects of different surgical therapies and robotic-assisted N Engl J Med.22). medroxyprogesterone acetate. 9.43 A meta-analysis of 14 randomized.
randomized. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript GUIDELINES Several professional organizations have published guidelines for the evaluation and treatment of endometriosis-related pain and infertility. or complementary medicine approaches14. p. Warner ML. Laparoscopy would be indicated to evaluate and treat persistent pain. [PubMed: 19144942] N Engl J Med. and family history has been obtained.. or both. and pain transmission. the patient should undergo transvaginal ultrasonography to look for an ovarian endometrioma or other pelvic disease. warrant further study. If the pain persists. Epidemiology of endometriosis. NSAIDs and cyclical combined oral contraceptives are recommended as first-line therapy in the absence of contraindications.50 and small observational studies suggest reductions in endometriosis-associated pain after transcutaneous electrical nerve stimulation. It is uncertain whether leaving endometriosis untreated accelerates the age-related decline in fertility. infertility. Goldstein DP. however. . If these approaches are not effective. 2009. Burney Endometriosis. In: Jameson. New York: 2010. selective progesterone-receptor modulators) and systemic immune dysfunction. deCholnoky C. 360:268–79. Obstet Gynecol Clin North Am...Giudice Page 6 laparoscopy on pain and fertility. 24:235–58. Endocrinology. Emans SJ. De Groot. physical therapy. including psychological support. and assessing the effects of different add-back therapies on pain and on bone density. Eskenazi B. In patients such as the woman described in the vignette. CONCLUSIONS AND RECOMMENDATIONS The patient described in the vignette has symptoms of pain that are highly suggestive of endometriosis. Table 2 lists key recommendations of these societies. a pelvic mass. If the pelvic examination reveals adnexal pain or tenderness with or without fullness. inflammation. shamcontrolled trial involving 18 adolescents and young women showed the efficacy of Japanese-style acupuncture for endometriosis-related pain.51 which involve a multidisciplinary approach. hypogastric nerve block. 2.g. Giudice. a pelvic examination should be performed. as compared with each other and with medical therapies. including a neuropathic component.19. a switch to continuous combined oral contraceptives for 3 to 6 months or a levonorgestrel intrauterine system is warranted. Oral GnRH antagonists and other small molecules that suppress circulating estradiol levels to the range suggested by the estrogen threshold hypothesis (30 to 45 pg per milliliter)49 also warrant investigation. N Engl J Med. RO.. The recommendations provided here are generally concordant with these guidelines. LM. data from large. Author manuscript. 1980. Bulun SE. controlled trials to confirm these findings are lacking. therapies aimed at correcting progesterone resistance (e. as well as those targeting angiogenesis. although peritoneal disease will not be detected by this imaging method. 1997.18. 6th ed. Studies of complementary or alternative therapies are needed. but she should also be reassured that she may not have a problem conceiving and that treatment for endometriosisassociated infertility is often effective. Endometriosis. surgical. neurotropism.. [PubMed: 9163765] 4. 2356-70. A randomized. The patient should be counseled about the association of endometriosis with infertility. editors. REFERENCES 1.16. Leventhal JM. for women with chronic pelvic pain. J Reprod Med. or both. After a thorough medical. Although the pathogenesis of endometriosis and associated pain and infertility remains incompletely understood. GnRH agonist therapy with estrogen–progestin add-back therapy is appropriate. JL. Elsevier. LJ. LC.25. [PubMed: 6448296] 3. Laparoscopy in the diagnosis and management of pelvic pain in adolescents. available in PMC 2011 June 6. Swiersz. 24:251–6. gynecologic.
Missmer SA.2010 Epub ahead of print. [PubMed: 16982655] 15. [PubMed: 12969698] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript N Engl J Med. et al. 2008. Barbieri RL. Montgomery GW. Treatment of pelvic pain associated with endometriosis. Lijmer JG. 4:CD004753. 2007. [PubMed: 15466501] 10. Giudice LC. Hum Reprod. Hum Reprod. [PubMed: 16950827] 7. Spiegel-man D. Am J Obstet Gynecol. Hum Reprod. randomized trial. March 23. 13:395–404. 1996. 1991. available in PMC 2011 June 6. Hum Reprod. Pain. [PubMed: 8671344] 25. Hoshiai H. 21:2743–8. De Giorgi O. Endocr Rev. Kinkel K. anthropometric. Malspeis S. Allen C. [PubMed: 15980014] 26. Obstet Gynecol. 2009. 103:589–605. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled. [PubMed: 9418699] 14. et al. 2008. 80:560–3. Fertil Steril. 2005. 2004. Barbieri RL. Kennedy S. Sanfilippo JS. Haines P. Vercellini P. 20:2698–704. [PubMed: 17584822] 16. Brosens I. Campo R.Giudice Page 7 5. Hum Reprod Update. Prentice A. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. The performance of CA-125 measurement in the detection of endometriosis: a meta-analysis. pelvic pain and dysmenorrhea in endometriosis. 2003. Nonsteroidal antiinflammatory drugs for pain in women with endometriosis. 1997. 82:1501–8. 13. [PubMed: 16235379] 27. Hummelshoj L. Best Pract Res Clin Obstet Gynaecol. The pains of endometriosis. [PubMed: 15947176] 6. Fertil Steril. Kennedy S. Bergqvist A. Fertil Steril. 308:1587–9. Sutton CJ. Practice Committee of the American Society for Reproductive Medicine. Wakim NG. Zhao ZZ. 2004. 1998. 51: chronic pelvic pain. 67:817–21. and lifestyle factors. 86(Suppl):S156–S160. 132(Suppl 1):S22– S25. 2004. ACOG Practice Bulletin no. 90(Suppl):S260– S269. Hum Reprod. 2005. Harada T. J Reprod Med. Marshall LM. 1986. Tracey DJ. [PubMed: 15157643] 23. Bayram N. Hunter DJ. Missmer SA. et al. Hummelshoj L. Rapkin AJ. Pietropaolo G. Follow-up report on a randomized controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal to moderate endometriosis. Moalem-Taylor G. D'Hooghe T. Ripps BA. 36:470–2. Hankinson SE. 68:1070–4. Endometriosis and infertility. 1997. [PubMed: 18535005] 12. Gordts S. Frontino G. Author manuscript. 2004. ESHRE guideline for the diagnosis and treatment of endometriosis. Markham R. Evans S. 11:878–80. A prospective study of dietary fat consumption and endometriosis risk. 30:293–342. Hankinson SE. Pooley AS. Science. Am J Epidemiol. Simoens S. Spiegel-man D. Chavarro JE. Pasin R. 2007. Mol BW. [PubMed: 9130884] 22. Cochrane Database Syst Rev. Ewen SP. 2005. Focal pelvic tenderness. Barlow D. Chapron C. Endometriosis: cost estimates and methodological perspective. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen. Fertil Steril. 160:784–96. 154:39–43. Schikler KN. [PubMed: 15589850] 9. [PubMed: 17055813] 19. [PubMed: 1941783] 18. Papka RE. Momoeda M. In utero exposures and the incidence of endometriosis. Tokushige N. Terakawa N. Russell P. [PubMed: 17761388] 21. Fertil Steril. et al. 70:1101–8. Diagnosis of endometriosis: pelvic endoscopy and imaging techniques. Fertil Steril. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Idem. Multi-disciplinary centres/networks of excellence for endometriosis management and research: a proposal. 21:3001–7. double-blind. 90:1583–8. [PubMed: 19007642] 20. Fraser IS. Mardon H. Delay in the diagnosis of endometriosis: a survey of women from the USA and the UK. Missmer SA. Incidence of laparoscopically confirmed endometriosis by demographic. . Hum Reprod Update. D'Hooghe T. Crosignani PG. 2006. Michels KB. Hopewell S. Taketani Y. [PubMed: 9848302] 24. Endometriosis in association with uterine anomaly. Bourguignon JP. 2006. Nyholt DR. 2006. Hadfield R. Pain and endometriosis. Diamanti-Kandarakis E. 14:447–57. [PubMed: 3946502] 8. [PubMed: 19502515] 11. Berkley KJ. et al. The search for genes contributing to endometriosis risk. [PubMed: 14990428] 17. Fertil Steril. Martin DC. Fertil Steril. Hunter DJ. 18:285–303. [PubMed: 18164001] 28. Yussman MA. Nerve fibres in peritoneal endometriosis. Puttemans P. 2008.
[PubMed: 11056151] 48. Vincent K. 2002.Giudice Page 8 29. Author manuscript. 68:393–401. available in PMC 2011 June 6. 2008. J Pediatr Adolesc Gynecol. Cochrane Database Syst Rev. Proctor ML. Cochrane Database Syst Rev. Collins JJ. Farquhar C. Farquhar C. Hajeer A. [PubMed: 9895397] 44. Casino LA. Obstet Gynecol. Hart RJ. Kennedy S. Hum Reprod. Stratton P. Progestins for symptomatic endometriosis: a critical analysis of the evidence. 2007. [PubMed: 19160262] 33. Smith SK. Cochrane Database Syst Rev. Am J Obstet Gynecol. Cochrane Database Syst Rev. Pain scoring in endometriosis: entry criteria and outcome measures for clinical trials: report from the Art and Science of Endometriosis meeting. 2005. 4:CD001896. 4:CD005072. 2000. Yates D. et al. Struthers RS. 20:293–7. Fertil Steril. Hassan S. Crosignani PG. Furness S. 2003. [PubMed: 18990378] 49. Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density. Cochrane Database Syst Rev. Hickey M. 2002. Nicholls AJ. 4:CD001300. 1:CD004635. Guzick DS. 15:2447–8. 2007. 4:CD001398. Hormone treatment endometriosis: the estrogen threshold hypothesis. [PubMed: 1536260] 34. Johnson NP. Buckett W. Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev. Barlow DH. 1997. 2009. Leuprolide acetate depot and hormonal addback in endometriosis: a 12-month study. Abou-Setta AM. Hormone therapy for endometriosis and surgical menopause. 2008. [PubMed: 19821276] 39. [PubMed: 15266496] 42. Jacobson TZ. Farquhar CM. 93:62–7. Nawathe A. [PubMed: 12057720] 45. [PubMed: 17054236] 31. Garcia-Velasco JA. N Engl J Med. Al Kadri H. Breeze A. 2004. Gordon CM. Latthe PM. Al-Inany HG. Laufer MR. Dunsmoor-Su R. Divasta AD. Cortesi I. Fertil Steril. 2:CD004992. Garry R. . Barbieri RL. Vandekerckhove P. Duffy JM. 1998. 1992. et al. Dias S. Arici A. Fedorkow DM. [PubMed: 10796530] 32. Coutifaris C. Farquhar CM. Khan KS. 91:16–24. [PubMed: 16235288] 41. Farmer JE. Olive D. Sallam HN. Maouris P. Barlow D. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. 94:545–51. 77:1148–55. 1999. J Clin Endocrinol Metab. [PubMed: 9314903] 30. Prentice A. 340:177–83. Weisberg GW. Pre and post operative medical therapy for endometriosis surgery. [PubMed: 18425908] 40. Deary AJ. Barnhart K. 2:CD000346. Patwardhan S. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. Laparoscopic surgery for subfertility associated with endometriosis. [PubMed: 16437491] 46. [PubMed: 12519555] 47. Cochrane Database Syst Rev. Khan KS. Goldbeck-Wood S. Laparoscopic surgery for pelvic pain associated with endometriosis. Cochrane Database Syst Rev. [PubMed: 18485158] 38. Surrey ES. Effect of endometriosis on in vitro fertilization. 2009. Koninckx PR. 2010. Brown J. 2006. Fertil Steril. Harrison GR. Prentice A. [PubMed: 19033369] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript N Engl J Med. Vercellini P. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. Koninckx PR. Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix. Hornstein MD. Yap C. BJOG. 4:CD001297. 2009. Sagsveen M. 3:CD000155. 3:CD003678. Ovulation suppression for endometriosis. 166:740–5. Al-Fozan HM. Carson SA. Farquhar C. 2000. Levonorgestrel-releasing intrauterine device (LNGIUD) for symptomatic endometriosis following surgery. Cochrane Database Syst Rev. [PubMed: 17636607] 43. [PubMed: 14583930] 36. Jacobson TZ. Bone density in adolescents treated with a GnRH agonist and add-back therapy for endometriosis. Al-Inany HG. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Grundy J. Coutifaris C. 2006. Cochrane Database Syst Rev. Cochrane Database Syst Rev. [PubMed: 9464714] 35. [PubMed: 17868896] 37. 115:818–22. 1:CD005997. Evidence may change with more trials: concepts to be kept in mind. Hughes E. Farquhar C.
Kerr CE. et al. Obstet Gynecol. Author manuscript.Giudice Page 9 50. ACOG committee opinion: number 310. . [PubMed: 18794019] 51. 2008. 21:247–57. [PubMed: 15802438] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript N Engl J Med. available in PMC 2011 June 6. 2005. Schnyer RN. 105:921–7. Japanese-style acupuncture for endometriosis-related pelvic pain in adolescents and young women: results of a randomized sham-controlled trial. J Pediatr Adolesc Gynecol. Wayne PM. April 2005: endometriosis in adolescents.
this color is not specific to endometriomas. University of California. Christopher Herndon. a hemorrhagic cyst. Author manuscript. Panel B shows peritoneal implants. .Giudice Page 10 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1. Panel D shows an endometrioma adherent to the posterior uterus and distending the ovarian capsule. including red and blue–black lesions and adhesions. San Francisco. the name “chocolate cysts”). available in PMC 2011 June 6.) N Engl J Med. Although the cyst fluid in endometriomas is thick and dark brown because it contains hemosiderin (hence. or a simple cyst. adhesions. it is difficult to distinguish visually an endometrioma from a cyst of the corpus luteum. (Images courtesy of Dr. At surgery. Peritoneal Lesions and an Ovarian Endometrioma Due to Endometriosis Panel A shows an endometriotic implant (red lesion). Panel C shows extensive adhesions distorting the normal pelvic anatomy. and hyperemia in the peritoneum.
and promote sprouting of nociceptors that contribute to persistent inflammatory pain and inhibit neuronal apoptosis.Giudice Page 11 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 2. neurotrophic peptides (nerve growth factor [NGF]). which decreases macrophage adhesion and phagocytic function. They are infiltrated by sensory. and thus the endometrium is inhospitable to an implanting embryo. Endocrine-disrupting chemicals can contribute to progesterone resistance and perhaps immune dysfunction. Infertility results from the toxic effects of the inflammatory process on gametes and embryos.1. also secrete proinflammatory cytokines (interleukin-1β.4 ERFFI1 (ErbB receptor feedback inhibitor 1) is constitutively expressed and there is excess mitogenic signaling. Pathophysiology of Pain and Infertility Associated with Endometriosis Retrograde transplanted endometrial tissue and cells attach to peritoneal surfaces. which can activate pain fibers. compromised fimbrial function. Author manuscript. Endometrial bleeding factor (EBAF) is misexpressed and may contribute to uterine bleeding. agents that attract macrophages (monocyte chemotactic protein 1 [MCP-1]). and invade nearby structures. interleukin-6. interleukin-8. Lesions and activated macrophages. available in PMC 2011 June 6. . Local (and systemic) estradiol can stimulate lesion production of PGE2. establish a blood supply. Endometriotic implants secrete estradiol (E2) as well as prostaglandin E2 (PGE2). and parasympathetic nerves and elicit an inflammatory response. enhance neuronal invasion of lesions by stimulating production of NGF and other neurotrophins. N Engl J Med. Lesions secrete haptoglobin. which are abundant in the peritoneal fluid in women with endometriosis. and tumor necrosis factor α [TNF-α]). enzymes for tissue remodeling (matrix metalloproteinases [MMPs]) and tissue inhibitors of MMPs (TIMPs). and proangiogenic substances such as vascular endothelial growth factor (VEGF) and interleukin-8. HoxA10 and HoxA11 genes and αVβ3 integrin are not up-regulated by progesterone. sympathetic. and eutopic endometrium that is resistant to the action of progesterone and is inhospitable to embryonic implantation.
and the blue and green areas indicate blood flow away from the transducer. Christopher Herndon. with little flow to the mass but normal flow to the ovary.) N Engl J Med. . available in PMC 2011 June 6. and orange areas indicate blood flow toward the transducer. University of California. (Images courtesy of Dr. The red. Author manuscript.Giudice Page 12 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 3. The T2-weighted magnetic resonance image in Panel B shows a left ovarian endometrioma (asterisk). San Francisco. yellow. Radiographic Images of Endometriomas The transvaginal ultrasonogram in Panel A shows the ground-glass appearance of a 5-cm right ovarian endometrioma.
edema. breast tenderness. not FDAapproved for endometriosis FDA-approved for endometriosis pain.Giudice Page 13 Table 1 Medical and Surgical Therapies for Endometriosis-Related Pelvic Pain. estrogen-progestin add-back therapy used to mitigate loss of bone mineral density Combined with progestagens. . and GnRH agonists because ovulation may be induced. can be used for up to 5 yr. fluid retention. gastrointestinal irritation. available in PMC 2011 June 6. fluid retention. delayed return of ovulation Bloating. amenorrhea. weight gain. decreased libido. decreased menstrual flow Nausea. weight gain. amenorrhea Continuous Dysmenorrhea. breakthrough bleeding.* Treatment Medical therapy NSAIDs Dysmenorrhea First-line Nausea. breast tenderness Especially beneficial for symptomatic rectovaginal endometriosis. not FDA-approved for endometriosis pain Side effects limit widespread use Levonorgestrel intrauterine system Dysmenorrhea. vomiting. depression. drowsiness.or third-line GnRH agonists Dysmenorrhea. Author manuscript. vaginal dryness. dyspareunia Second. loss of bone mineral density) Hypoestrogenism. depression. breast tenderness. decreased breast size) Surgical therapy N Engl J Med. fluid retention. headache. headache. noncyclic chronic pelvic pain Third-line Danazol Dysmenorrhea. weight gain. dyspareunia Second. hypomenorrhea or amenorrhea for 6–12 mo. combined oral contraceptives. breakthrough bleeding. irritability. noncyclic chronic pelvic pain Second. depression.or third-line Hypoestrogenism (vasomotor symptoms. breakthrough bleeding.or third-line Hyperandrogenic side effects (acne. headache Initiate treatment at beginning of or just before menses. noncyclic chronic pelvic pain Second-line Nausea. somewhat decreased menstrual flow Indication Type of Therapy Side Effects and Complications Comments NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Combined oral contraceptives Cyclic Dysmenorrhea First-line Nausea. weight gain. headache. induction of ovulation Aromatase inhibitors Dysmenorrhea. noncyclic chronic pelvic pain Second-line Progestins Medroxyprogesterone acetate Dysmenorrhea.
N Engl J Med. Author manuscript. fluid retention. LPSN laparoscopic presacral neurectomy. dyspareunia First-or second-line Risk associated with anesthesia and risk of infection. danazol. breakthrough bleeding. depression. and excision Indication Type of Therapy Side Effects and Complications Comments NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript * Dysmenorrhea. hemorrhage Risk associated with anesthesia and risk of infection. constipation. and NSAID nonsteroidal antiinflammatory drug. weight gain. edema. headache FDA denotes Food and Drug Administration. new adhesions. damage to internal organs. ablation. should be performed by surgeons with experience in LPSN Reoperation may be necessary. fluid retention. breakthrough bleeding. dyspareunia. breast tenderness. deep central pain Third-line Hysterectomy. weight gain. measure FSH level to check ovarian remnant. . noncyclic chronic pelvic pain. decreased breast size). available in PMC 2011 June 6. total. nerve-pathway interruption (with conservative surgery) Dysmenorrhea. urinary urgency. residual ovarian tissue First-line therapy for pelvic mass. new adhesions. chronic pelvic pain First-line LPSN.Giudice Page 14 Treatment Laparoscopy Fulguration. FSH follicle-stimulating hormone. commonly secondline therapy for pelvic pain resistant to medical therapy Potential for decreased ovarian reserve. laparoscopic. add progestin to postoperative estrogenreplacement therapy for vasomotor symptoms Excision or drainage and ablation Endometrioma >3 cm in diameter. excision is preferable to drainage and ablation Technically challenging surgery. bilateral oophorectomy (abdominal. or supracervical) Noncyclic chronic pelvic pain Fourth-line Adjunctive medical therapy after conservative surgery GnRH agonist Dysmenorrhea. noncyclic chronic pelvic pain Dysmenorrhea Third-line Hypoestrogenism Used primarily in stage III or IV disease Not commonly used Medroxyprogesterone acetate. painless first-stage labor Persistent or recurrent pain in 10% of patients. hemorrhage Bleeding in the adjacent venous plexus. danazol: hyperandrogenic side effects (acne. combined oral contraceptives Third-line Medroxyprogesterone acetate: nausea. depression. GnRH gonadotropin-releasing hormone. combined oral contraceptives: nausea. damage to internal organs.
Initial treatment is a trial of nonsteroidal antiinflammatory drugs and hormonal therapy (combined oral contraceptives).Giudice Page 15 Table 2 Major Guidelines from Professional Societies for the Diagnosis and Management of Endometriosis-Related Pain and Infertility. † Data on the diagnosis and management of chronic pelvic pain16 and on the treatment of adolescents with pelvic pain51 are from the American College of Obstetricians and Gynecologists..25 GnRH denotes gonadotropin-releasing hormone. although there is potential for diminished ovarian reserve. Recommendation NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Treatment Infertility Diagnosis Treatment Both the male and female partner should undergo a full evaluation. The levonorgestrel intrauterine system is effective in selected patients. All hormonal drugs that have been studied (combined oral contraceptives. The use of a GnRH agonist for 3–6 mo before in vitro fertilization and surgical ablation of endometriosis for stage I or II disease are beneficial.3 cm in diameter is of benefit. There should be a low threshold for the evaluation of endometriosis in adolescents because the diagnosis is often missed in this age group. If a GnRH agonist is used. Superovulation with intrauterine insemination provides a benefit. and danazol) are similarly effective.g.* Condition Pain† Diagnosis Surgery is the preferred method for the diagnosis of pelvic pain and a pelvic mass (e. . Author manuscript. Laparoscopic uterosacral nerve ablation is not effective. endometrioma). estrogen-progestin add-back therapy is recommended. available in PMC 2011 June 6. * Guidelines are from the American Society for Reproductive Medicine18. but their side effects and costs differ. but it is not required before initiating empirical therapy.19 and the European Society of Human Reproduction and Embryology. GnRH agonists are not recommended for adolescents because of their effects on bone. Ovarian suppression is not effective in promoting spontaneous pregnancy. N Engl J Med. after consideration of other conditions in a differential diagnosis. Excision of endometriomas >. progestins. GnRH agonists.
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue reading from where you left off, or restart the preview.